When administered orally, by swallowing a tablet or capsule, for example, some drugs undergo significant hepatic first-pass metabolism. Hepatic first-pass metabolism is sometimes undesirable. It is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before systemic blood circulation and delivery to the target tissue. In effect, hepatic first-pass metabolism reduces the amount of drug that reaches the target tissue. Thus oral delivery of drugs affected by hepatic first-pass metabolism is inefficient and results in poor bioavailability. In addition, first-pass metabolism may result in fluctuations in plasma drug level and high plasma levels of drug metabolites, which can be undesirable for various reasons.
Another challenge of oral administration is that some drugs may be sensitive to the acidic pH or digestive enzymes found in the stomach or other parts of the gastrointestinal tract. Thus, oral administration of these drugs for absorption in the gastrointestinal tract is not optimal.
Non-oral routes, such as intravenous or intramuscular injection, can bypass the gastrointestinal tract, and hepatic first-pass metabolism. However, these methods of administration often result in poor patient compliance due to patient aversions to injections. In addition, many injectable dosage forms must be administered by a healthcare professional, requiring additional costs and the inconvenience of scheduling and traveling to the healthcare professional.
Other non-oral routes, such as transdermal administration using an ointment or patch, or nasal routes, can result in incomplete absorption and irritation at the site of administration.
The administration of drugs orally in a dosage form that releases the drug in the mouth and allows the drug to absorbed across the oral mucosa (i.e., the oral transmucosal route), circumvents the gastrointestinal tract and hepatic first-pass metabolism. However, the design and making of oral transmucosal formulations faces challenges, particularly for drugs that are poorly soluble in water.
In typical oral transmucosal formulations, the drug particle is in crystalline or particulate form embedded in a matrix in the dosage form. The absorption of a drug from such a dosage form, particularly of drugs that are poorly soluble in water, is inefficient for several reasons.
First, the crystalline drug requires a significant amount of energy from the mouth fluid (saliva) to break the bonds between its molecules to get dissolved.
Second, compared to the gastrointestinal tract, the mouth has limited fluid (saliva) to break the crystal bonds between the drug molecules, transform the drug from particulate matter into molecular form, and/or dissolve the drug, a prerequisite for permeation and absorption.
Third, compared to the gastrointestinal tract, the mouth has limited surface area (oral mucosa) for the dissolved drug to be permeated and absorbed.
Forth, compared to the gastrointestinal tract, the oral mucosa is less permeable.
Fifth, compared to the gastrointestinal tract, the mouth has limited residence time for the drug to be dissolved from the dosage form and to be permeated and absorbed through the oral mucosa.
In addition, currently available oral transmucosal buccal adhesive dosage forms are typically small tablets, having little surface area in contact with the oral mucosa. Thus, the drug is not well exposed to the entire oral mucosal surface resulting in only a small area over which the drug may diffuse after it dissolves. This feature can limit uptake of the drug.
For these reasons, many drug molecules cannot be delivered efficiently via the oral transmucosal route using currently known means, despite the advantages of using this route.
Oral transmucosal dosage forms face the challenges of reducing the energy required to break the crystal bonds between molecules of a drug, identifying an agent to reduce and maintain the reduced crystal bonds between molecules of a drug, and using a mathematical model to calculate a composition of a system comprising a drug having a desired extent or magnitude of the reduced crystal bonds between the molecules or a desired degree of the reduced crystallinity. Oral transmucosal dosage forms also face challenges of completely reducing the energy required to break the crystal bonds between molecules of a drug, and identifying an agent to maintain the completely or substantially decrystallized form of a drug.
In addition, oral transmucosal dosage forms face challenges of overcoming the physical barrier of the oral mucosal membrane, increasing the drug permeability across the oral mucosal membrane and delivering the drug with sufficient bioavailability.
The making of oral transmucosal dose forms faces challenges of creating the reduced crystal bonds between molecules of a drug, achieving a dosage form comprising a drug having the reduced bonds between molecules, and maintaining the physic-chemical stability of the dosage form comprising a drug having the reduced bonds between molecules throughout its shelf life.
The making of oral transmucosal dose forms also faces challenges of achieving a dosage form comprising a drug having a completely or substantially decrystallized form, and maintaining the physico-chemical stability of the dosage form comprising a drug having a completely or substantially decrystallized form throughout its shelf life.
In addition, the administering of oral transmucosal dose forms faces challenges of achieving ease of administration of such a dosage form, achieving a desired dosing frequency of such a dosage form and achieving patient compliance for such a dosage form.
Some drugs for which transmucosal delivery would be highly beneficial include testosterone administered to testosterone-deficient men, and bioidentical hormones used for hormone replacement therapy in perimenopausal and menopausal women.
Transdermal and transmucosal testosterone containing dosage forms are available on the market, but are not optimal.
Some men using testosterone gel or transdermal patches experience skin irritation at the application site. (See prescribing information for ANDROGEL® testosterone gel, FORTESTA® testosterone gel, TESTIM® testosterone gel, and ANDRODERM® testosterone transdermal system).
Another concern with testosterone gel is direct skin-to-skin transfer, or clothing-to-skin transfer of this drug to another person who does not require testosterone therapy (e.g., a partner or a child) and who could suffer significant adverse events from testosterone exposure. In addition, there is the possibility of contamination of clothing or bed sheets contacted after application of the gel. (See prescribing information for ANDROGEL® testosterone gel, FORTESTA® testosterone gel, TESTIM® testosterone gel). If clothing or bed sheets are contaminated they could contaminate the clothes of women and children in the same household if these items are washed together. The product labeling for these products contain warnings about the potential for secondary exposure to testosterone. For example, labels state that “cases of secondary exposure resulting in virilization of children have been reported in post marketing surveillance of testosterone gel products.” (Id.) These product labels also contain extensive instructions about proper methods of administration to decrease the chance of this occurring. (Id.)
The available testosterone gel formulations are not bioequivalent to each other. They vary in bioavailability, with differing peak serum concentrations of testosterone (total testosterone, free testosterone, and dihydrotestosterone), as well as other pharmacokinetic differences.
A buccal bioadhesive testosterone tablet is also available, and provides transmucosal delivery. However, in one trial, 16% of hypogonadal men using the buccal bioadhesive tablet reported gum-related adverse events, including edema, gingivitis, inflammation, and blistering. (See prescribing information for STRIANT® testosterone tablet). Moreover, this buccal bioadhesive tablet provides only a limited contact area for drug absorption.
Other suitable drugs for oral transmucosal delivery are hormones used in Hormone Replacement Therapy (HRT) for menopausal women. These drugs include estrogens (e.g., 17 β-estradiol, estradiol acetate, and estradiol hemihydrates) and progestins (e.g., progesterone, and norgestimate, and levonorgestrel) and combinations of these drugs. These drugs are given in various types of dosage forms, including oral tablets; vaginal rings, creams, gels or tablets; and transdermal cream, gels, or patches. There are disadvantages to each of these dosage forms. The disadvantages of oral tablets include that administration of these hormones orally may induce nausea. Disadvantages of current vaginal creams, gels, pills and rings are that they are limited to the treatment of vaginal symptoms, and are not very effective for other effects of menopause, such as bone loss, and hot flashes.
Other disadvantages of gels and creams are that they can be messy, and require attention that the correct amount is applied to ensure appropriate dosing. For creams administered to the thigh, skin must be dry and the cream must be massaged deeply into the skin. It is easier to ensure that a patient administer a complete dose if the drug is delivered in an oral solid dosage form, such as a pill or lozenge. Also dermal application of dosage form suffers from variable and unpredictable absorption due to location applied, variation in body hair, sweating, hygiene, dryness, wetness etc.
Administration of these “bioidentical hormones” by the oral transmucosal route could avoid the first pass effect, and may reduce the incidence of nausea, a common side effect of orally administered HRT, could provide systemic effects for complaints other than vaginal dryness and thinning, and could avoid the potential for incorrect dosing of creams and gels.